The invention relates to the subject that is characterized in the claims, i.e., macrocyclic perfluoroalkylamides, their production and their use in diagnosis.
In nuclear magnetic resonance, the element fluorine is second in importance to the element hydrogen.
1. Fluorine has a high sensitivity of 83% of that of hydrogen.
2. Fluorine has only one NMR-active isotope.
3. Fluorine has a resonance frequency that is similar to hydrogenxe2x80x94fluorine and hydrogen can be measured with the same system.
4. Fluorine is biologically inert.
5. Fluorine does not occur in biological material (exception: teeth) and can therefore be used as a probe or contrast medium against a background that is free of interfering signals.
The effect of these properties is that fluorine occupies a broad space in diagnostic patent literature with nuclear magnetic resonance as a basis: fluorine-19-imaging, functional diagnosis, spectroscopy.
U.S. Pat. No. 4,639,364 (Mallinckrodt) thus proposes trifluoromethanesulfonamides as contrast media for fluorine-19-imaging:
CF3SO2NH2
CF2SO2NHxe2x80x94CH2xe2x80x94(CHOH)4xe2x80x94CH2OH
German Patent DE 4203254 (Max-Planck-Gesellschaft), in which an aniline derivative is proposed, also relates to fluorine-19-imaging: 
Fluorine-19-imaging is the subject of application WO 93/07907 (Mallinckrodt), in which phenyl derivatives are also claimed as contrast media: 
Compounds of considerably simpler structure are also claimed for fluorine-19-imaging. Thus, U.S. Pat. No. 4,586,511 (Children""s Hospital Medical Center) mentions perfluorooctyl bromide
CF3(CF2)7xe2x80x94Br
European Patent EP 307863 (Air Products) mentions perfluoro-15-crown-ether 
and U.S. Pat. No. 4,588,279 (University of Cincinnati, Children""s Hospital Research Foundation) mentions perfluorocarbon compounds, such as perfluorocyclononane or -octane, perfluorinated ethers such as tetrahydrofuran 
or diethers such as perfluoro-propyleneglycol-diether 
The compounds that are mentioned in Application WO 94/22368 (Molecular Biosystems), e.g., 
which as fluorine-containing radicals have the perfluoro-1H,1H-neopentyl group, are also used for fluorine-19-imaging.
U.S. Pat. No. 5,362,478 (VIVORX) indicates another structural type with expanded diagnostic use, in which the fluorocarbon/polymer shell combination is claimed for imaging purposes. Perfluorononane and human serum albumin are mentioned. This combination proves suitable, moreover, for using the fluorine atom as a probe for local temperature measurement and for determining the partial oxygen pressure.
Perfluorocarbons are also claimed in U.S. Pat. No. 4,586,511 for oxygen determination.
In German Patent DE 4008179 (Schering), fluorine-containing benzenesulfonamides are claimed as pH probes: 
For NMR diagnosis, compounds that contain iodine and fluorine atoms are also claimed as contrast-enhancing agents in WO 94/05335 and WO 94/22368 (both molecular biosystems): 
The fluorine-paramagnetic metal ion combination is also claimed for fluorine-19-imaging, specifically for open-chain complexes in WO 94/22368 (Molecular Biosystems) with, e.g.: 
and in EP 292 306 (TERUM Kabushiki Kaisha) with e.g.: 
but also for cyclic compounds, as they are mentioned in EP 628 316 (TERUMO Kabushiki Kaisha) 
The fluorine atom-rare earth metal combination is also claimed for NMR-spectroscopic temperature measurements in DE 4317588 (Schering). 
Ln: Rare earths: La, Pr, Dy, Eu
While no interactions between the two nuclei occur in compounds that contain the elements fluorine and iodine, intensive interaction does occur in compounds that contain fluorine and paramagnetic centers (radicals, metal ions), which are expressed in a shortening of the relaxation time of the fluorine nucleus. The extent of this effect depends on the number of unpaired electrons of the metal ion (Gd3+ greater than Mn2+ greater than Fe3+ greater than Cu2+) and on the removal between the paramagnetic ion and the 19F atom.
The more unpaired electrons of the metal ion are present and the closer they are brought to the fluorine, the greater the shortening of the relaxation time of the fluorine nucleus.
The shortening of the relaxation time as a function of the distance from the paramagnetic ion becomes apparent in all nuclei with an uneven spin number, thus also in the case of protons, and gadolinium compounds; therefore, there is wide use as contrast media in nuclear spin tomography (Magnevist(R), Prohance(R), Omniscan(R), Dotarem(R)).
In 1H-MR imaging (1H-MRI), however, relaxation time T1 or T2 of the protons, i.e., mainly the protons of water and not the relaxation time of the fluorine nuclei, is measured and used for imaging. The quantitative measurement for the shortening of the relaxation time is relaxivity [L/mmol s]. Complexes of paramagnetic ions are successfully used for shortening the relaxation times. In the following table, the relaxivity of some commercial preparations is indicated:
In these compounds, only interactions between protons and the gadolinium ion occur. For these contrast media in water, a relaxivity of about 4 [L/mmolxc2x7s] is thus observed.
Both fluorine compounds for fluorine-19-imaging, in which the shortened relaxation time of the fluorine nucleus is used, and non-fluorine-containing compounds, in which the relaxation time of the protons of water is measured, are thus used successfully for MR imaging.
In the introduction of a perfluorocarbon-containing radical into a paramagnetic contrast medium, i.e., in the combination of properties that were previously known as suitable only for fluorine-imaging compounds, the relaxivity that relates to the protons of water also increases rapidly, surprisingly enough, with compounds that were used for proton imaging. It now reaches values of 10-50 [L/mmolxc2x7s] in comparison to values between 3.5 and 3.8 [L/mmolxc2x7s] as they were already cited for some commercial products in the table above.
Perfluoroalkyl-containing metal complexes are known from DE 196 03 033.1. The compounds of this invention are distinguished, however, by better properties, such as, for example, higher lymph node accumulation in three successive lymph node stations, better elimination, greater compatibility (which is especially advantageous for i.v. lymphography) and very good local compatibility in the case of interstitial administration. This opens up the possibility of adding the compounds at higher doses.
The MRI contrast media are used mainly for the visualization of malignant tumors.
Malignant tumors metastasize in clusters in regional lymph nodes, whereby multiple lymph node stations may also be involved. Thus, lymph node metastases are found in about 50-69% of all patients with malignant tumors (Elke, Lymphographie [Lymphography], in: Frommhold, Stender, Thurn (Eds.), Radiologische Diagnostik in Klinik und Praxis [Radiological Diagnosis in Clinical Studies and Practice], Volume IV, Thieme Verlag Stuttgart, 7th Edition, 434-496, 1984)). The diagnosis of a metastatic attack of lymph nodes is of great importance with respect to the therapy and prognosis of malignant diseases. With modern imaging methods (CT, US and MRI), lymphogenous metastases of malignant tumors are detected only inadequately, since in most cases, only the size of the lymph node can be used as a diagnostic criterion. Thus, small metastases in non-enlarged lymph nodes ( less than 2 cm) cannot be distinguished from lymph node hyperplasias without a malignant attack (Steinkamp et al., Sonographie und Kernspintomographie; Differential Diagnostik von reaktiver Lymphknotenvergrxc3x6xcex2erung und Lymphknotenmetastasen am Hals [Sonography and Nuclear Spin Tomography: Differential Diagnosis of Reactive Lymph Node Enlargement and Lymph Node Metastases on the Neck], Radiol. Diagn. 33: 158, 1992).
It would be desirable if lymph nodes with metastatic attack and hyperplastic lymph nodes can be distinguished with use of specific contrast media.
Direct x-ray lymphography (injection of an oily contrast medium suspension into a prepared lymph vessel) is known as an invasive method that is used only infrequently and that can visualize only small lymphatic drainage stations.
Fluorescence-labeled dextrans are also used experimentally in animal experiments to be able to observe lymphatic drainage after their interstitial administration. All commonly used markers for the visualization of lymph tracts and lymph nodes after interstitial/intracutaneous administration have in common the fact that they are substances with a particulate nature (xe2x80x9cparticulates,xe2x80x9d e.g., emulsions and nanocrystal suspensions) or large polymers (see above, WO 90/14846). Based on their inadequate local and systemic compatibility as well as their small lymphatic passageway, which causes inadequate diagnostic efficiency, however, the previously described preparations prove to be still not optimally suitable for indirect lymphography.
Since the visualization of lymph nodes is of central importance for early detection of the metastatic attack in cancer patients, there is a great need for lymph-specific contrast medium preparations for diagnosis of corresponding changes of the lymphatic system.
The highest possible contrast medium concentration and high stability are just as desirable as the diagnostically relevant, most uniform possible lymphatic concentration over several lymph stations. The burden on the overall organism should be kept low by quick and complete excretion of the contrast medium. A quick start-up, if possible as early as within a few hours after the administration of contrast media, is important for the radiological practice. Good compatibility is necessary.
The object of the invention is achieved by the macrocyclic perfluoroalkyl compounds of general formula I 
in which
K means a complexing agent or a metal complex of general formula II 
xe2x80x83whereby
R1 stands for a hydrogen atom or a metal ion equivalent of atomic numbers 21-29, 31, 32, 37-39, 42-44, 49 or 57-83,
R2 and R3 stand for a hydrogen atom, a C1-C7 alkyl group, a benzyl group, a phenyl group, xe2x80x94CH2OH or xe2x80x94CH2xe2x80x94OCH3, and
U stands for radical L, whereby L and U, independently of one another, can be the same or different,
A means a hydrogen atom, a straight-chain or branched C1-C30 alkyl group, which optionally is interrupted by 1-15 oxygen atoms and/or optionally is substituted with 1-10 hydroxy groups, 1-2 COOH groups, a phenyl group, a benzyl group and/or 1-5 OR4 groups, with R4 in the meaning of a hydrogen atom or a C1-C7 alkyl radical, or xe2x80x94Lxe2x80x94RF,
L means a straight-chain or branched C1-C30 alkylene group, which optionally is interrupted by 1-10 oxygen atoms, 1-5 xe2x80x94NHxe2x80x94CO groups, 1-5 xe2x80x94COxe2x80x94NH groups, by a phenylene group that is optionally substituted by a COOH group, 1-3 sulfur atoms, 1-2 xe2x80x94N(B1)xe2x80x94SO2 groups, and/or 1-2 xe2x80x94SO2xe2x80x94N(B1) groups with B1 in the meaning of A, an N(B)xe2x80x94SO2 group or an xe2x80x94SO2xe2x80x94N(B)xe2x80x94 group, and/or optionally is substituted with radical RF, and
RF means a straight-chain or branched perfluorinated alkyl radical of formula CnF2nX,
whereby 4 is equal to or less than n, which is equal to or less than 20, and
X stands for a terminal fluorine atom, chlorine atom, iodine atom or a hydrogen atom, and optionally present acid groups optionally can be present as salts of organic and/or inorganic bases or amino acids or amino acid amides.
The new perfluoroalkyl-containing compounds of general formula I of claim 1 according to the invention comprise both complexing agents and metal complexes. Compounds of general formula I in which the metal ion equivalent that is bonded in macrocycle K is absent are referred to as complexing agents, and compounds with a metal ion equivalent that is bonded in macrocycle K are referred to as metal complexes.
As metal ion equivalents, and depending on the desired use of the compounds according to the invention, the following metals are suitable:
1. When used in NMR diagnosis and x-ray diagnosis: complexes with the ions of elements with atomic numbers 21-29, 39, 42, 44 and 57-83;
2. When used in radiodiagnosis and radiotherapy: complexes with the radioisotopes of elements with atomic numbers 27, 29, 31, 32, 37-39, 43, 49, 62, 64, 70, 75 and 77.
The ions of elements with atomic numbers 21-29, 39, 42, 44 and 57-83 are preferred.
Gadolinium is especially preferred.
Alkyl groups R2, R3, R4 can be straight-chain or branched. Methyl, ethyl, propyl, isopropyl, n-butyl, 1-methylpropyl, 2-methylpropyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl can be mentioned by way of example.
Hydrogen and C1-C4 alkyl groups, especially preferably hydrogen and the methyl group, are preferred for R2, R3 and R4.
The benzyl group and phenyl group R2, A and B1 can be substituted in the phenyl ring. As a substrate, the COOH group is suitable.
If the compound of formula I contains radicals L and U at the same time, L and U can be different from one another.
The C1-C30 alkylene groups U can be straight-chain or branched. Methylene, ethylene, propylene, isopropylene, n-butylene, 1-methylpropylene, 2-methylpropylene, n-pentylene, 1-methylbutylene, 2-methylbutylene, 3-methyl-butylene, 1,2-dimethylpropylene can be mentioned by way of example.
For U in the meaning of alkylene, C1-C10 alkylene groups are preferred; C1-C4 alkylene groups are especially preferred.
The C1-C30 alkyl groups A can be straight-chain or branched. Methyl, ethyl, propyl, isopropyl, n-butyl, 1-methylpropyl, 2-methylpropyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl, n-hexyl can be mentioned by way of example.
The C1-C30 alkyl groups A can be interrupted by 1-15 oxygen atoms and/or substituted with 1-10 hydroxy group, 1-5 alkoxy groups or 1-2 COOH groups, such as, e.g.,
C2H4xe2x80x94Oxe2x80x94CH3, C3H6xe2x80x94Oxe2x80x94CH3,
C2H4xe2x80x94Oxe2x80x94(C2H4xe2x80x94O)txe2x80x94C2H4xe2x80x94OH, C2H4xe2x80x94Oxe2x80x94(C2H4xe2x80x94O)txe2x80x94C2H4xe2x80x94OCH3 with t=0 to 13,
C2H4OH, C3H6OH, C4H8OH, C5H10OH, C6H12OH, C7H14OH, as well as their branched isomers,
CH(OH)CH2OH,
CH(OH)CH(OH)CH2OH, CH2[CH(OH)]uCH2OH, with u=1-10
CH[CH2(OH)]CH(OH)CH2OH,
C2H4CH(OH)CH2OH,
(CH2)sCOOH with s=1 to 15,
C2H4xe2x80x94Oxe2x80x94(C2H4xe2x80x94O)txe2x80x94CH2COOH with t=0 to 13,
C2H4xe2x80x94Oxe2x80x94(C2H4xe2x80x94O)txe2x80x94C2H4xe2x80x94CnF2nX with t=0 to 13, n=4 to 20 and X=a flourine, chlorine, bromine or iodine atom.
Preferred meanings for A are hydrogen, C1-C10 alkyl,
C2H4xe2x80x94Oxe2x80x94CH3, C3H6xe2x80x94Oxe2x80x94CH3,
C2H4xe2x80x94Oxe2x80x94(C2H4xe2x80x94O)xxe2x80x94C2H4xe2x80x94OH, C2H4xe2x80x94Oxe2x80x94(C2H4xe2x80x94O)xxe2x80x94C2H4xe2x80x94OCH3 with x=0 to 5,
C2H4OH, C3H6OH,
CH2[CH(OH)]yCH2OH, with y=1-6
CH[CH2(OH)]CH(OH)CH2OH,
(CH2)wCOOH with w=1 to 10,
C2H4xe2x80x94Oxe2x80x94(C2H4xe2x80x94O)xxe2x80x94CH2COOH with x=0 to 5,
C2H4xe2x80x94Oxe2x80x94(C2H4xe2x80x94O)xxe2x80x94C2H4xe2x80x94CpF2pX with x=0 to 5, p=4 to 15, and X=a fluorine atom.
If the compound of general formula I contains two radicals Lxe2x80x94RF, these radicals can be different from one another.
For radicals L, there can be mentioned by way of example, whereby xcex1 stands for the bond to the nitrogen atom and xcex2 stands for the bond to radical RF:
xcex1-(CH2)k-xcex2 with k=1-15
xcex1-CH2xe2x80x94CH2xe2x80x94(Oxe2x80x94CH2xe2x80x94CH2xe2x80x94)r-xcex2 with r=1-6
xcex1-CH2xe2x80x94(Oxe2x80x94CH2xe2x80x94CH2xe2x80x94)r-xcex2 with r=1-6
xcex1-CH2xe2x80x94NHxe2x80x94CO-xcex2
xcex1-CH2xe2x80x94CH2xe2x80x94NHxe2x80x94SO2-xcex2
xcex1-CH2xe2x80x94NHxe2x80x94COxe2x80x94CH2xe2x80x94N(CH2COOH)xe2x80x94SO2-xcex2
xcex1-CH2xe2x80x94NHxe2x80x94COxe2x80x94CH2xe2x80x94N(C2H5)xe2x80x94SO2-xcex2
xcex1-CH2xe2x80x94NHxe2x80x94COxe2x80x94CH2xe2x80x94N(C10OH21)xe2x80x94SO2-xcex2
xcex1-CH2xe2x80x94NHxe2x80x94COxe2x80x94CH2xe2x80x94N(C6H13)xe2x80x94SO2-xcex2
xcex1-CH2xe2x80x94NHxe2x80x94COxe2x80x94(CH2)10xe2x80x94N(C2H5)xe2x80x94SO2-xcex2
xcex1-CH2xe2x80x94NHxe2x80x94COxe2x80x94CH2xe2x80x94N(xe2x80x94CH2xe2x80x94C6H5)xe2x80x94SO2-xcex2
xcex1-CH2xe2x80x94NHxe2x80x94COxe2x80x94CH2xe2x80x94N(xe2x80x94CH2xe2x80x94CH2xe2x80x94OH)SO2-xcex2
xcex1-CH2xe2x80x94NHCOxe2x80x94(CH2)10xe2x80x94Sxe2x80x94CH2CH2-xcex2
xcex1-CH2NHCOCH2xe2x80x94Oxe2x80x94CH2CH2-xcex2
xcex1-CH2xe2x80x94CH2NHCOCH2xe2x80x94Oxe2x80x94CH2CH2-xcex2
xcex1-CH2xe2x80x94(CH2xe2x80x94CH2xe2x80x94O)rxe2x80x94(CH2)3NHCOxe2x80x94CH2xe2x80x94Oxe2x80x94CH2CH2-xcex2 with r=1-6
xcex1-CH2NHCO(CH2)10xe2x80x94Oxe2x80x94CH2CH2-xcex2
xcex1-CH2CH2NHCO(CH2)10xe2x80x94Oxe2x80x94CH2CH2-xcex2
xcex1-CH2xe2x80x94C6H4xe2x80x94Oxe2x80x94CH2CH2-xcex2 whereby phenylene group 1,4 or 1,3 is linked
xcex1-CH2xe2x80x94Oxe2x80x94CH2xe2x80x94C(CH2xe2x80x94OCH2CH2xe2x80x94C6F13)2xe2x80x94CH2xe2x80x94OCH2xe2x80x94CH2-xcex2
xcex1-CH2xe2x80x94NHCOCH2CH2CONxe2x80x94CH2CH2NHCOCH2N(C2H5)SO2C8F17xcex2
xcex1-CH2xe2x80x94CH2NHCOCH2N(C2H5)xe2x80x94SO2-xcex2
xcex1-CH2xe2x80x94Oxe2x80x94CH2xe2x80x94CH(OC10H21)xe2x80x94CH2xe2x80x94Oxe2x80x94CH2CH2-xcex2
xcex1-(CH2NHCO)4xe2x80x94CH2Oxe2x80x94CH2CH2-xcex2
xcex1-(CH2NHCO)3xe2x80x94CH2Oxe2x80x94CH2CH2-xcex2
xcex1-CH2xe2x80x94OCH2C(CH2OH)2xe2x80x94CH2xe2x80x94Oxe2x80x94CH2CH2-xcex2
xcex1-CH2NHCOCH2N(C6H5)xe2x80x94SO2-xcex2
xcex1-NHCOxe2x80x94CH2xe2x80x94CH2-xcex2
xcex1-NHCOxe2x80x94CH2xe2x80x94Oxe2x80x94CH2CH2-xcex2
xcex1-NHxe2x80x94CO-xcex2
xcex1-NHxe2x80x94COxe2x80x94CH2xe2x80x94N(CH2COOH)xe2x80x94SO2-xcex2
xcex1-NHxe2x80x94COxe2x80x94CH2xe2x80x94N(C2H5)xe2x80x94SO2-xcex2
xcex1-NHxe2x80x94COxe2x80x94CH2xe2x80x94N(C10H21)xe2x80x94SO2-xcex2
xcex1-NHxe2x80x94COxe2x80x94CH2xe2x80x94N(C6H13)xe2x80x94SO2-62
xcex1-NHxe2x80x94COxe2x80x94(CH2)10xe2x80x94N(C2H5)xe2x80x94SO2-xcex2
xcex1-NHxe2x80x94COxe2x80x94CH2xe2x80x94N(xe2x80x94CH2xe2x80x94C6H5)xe2x80x94SO2-xcex2
xcex1-NHxe2x80x94COxe2x80x94CH2xe2x80x94N(xe2x80x94CH2xe2x80x94CH2xe2x80x94OH)SO2-xcex2
xcex1-NHxe2x80x94COxe2x80x94CH2-xcex2
xcex1-CH2xe2x80x94Oxe2x80x94C6H4xe2x80x94Oxe2x80x94CH2xe2x80x94CH2-xcex2
xcex1-CH2xe2x80x94C6H4xe2x80x94Oxe2x80x94CH2xe2x80x94CH2-xcex2
xcex1-N(C2H5)xe2x80x94SO2-xcex2
xcex1-N(C6H5)xe2x80x94SO2-xcex2
xcex1-N(C10OH21)xe2x80x94SO2-xcex2
xcex1-N(C6H13)xe2x80x94SO2-xcex2
xcex1-N(C2H4OH)xe2x80x94SO2-xcex2
xcex1-N(CH2COOH)xe2x80x94SO2-xcex2
xcex1-N(CH2C6H5)xe2x80x94SO2-xcex2
xcex1-Nxe2x80x94[CH(CH2OH)2]xe2x80x94SO2-xcex2
xcex1-Nxe2x80x94[CH(CH2OH)CH(OH)(CH2OH)]xe2x80x94SO2-xcex2
Preferred are:
xcex1-CH2xe2x80x94Oxe2x80x94CH2CH2-xcex2
xcex1-CH2xe2x80x94CH2xe2x80x94(Oxe2x80x94CH2xe2x80x94CH2xe2x80x94)y-xcex2 with y=1-6
xcex1-CH2xe2x80x94(Oxe2x80x94CH2xe2x80x94CH2xe2x80x94)y-xcex2 with y=1-6
xcex1-CH2xe2x80x94CH2xe2x80x94NHxe2x80x94SO2-xcex2 Example 10
xcex1-CH2NHCOCH2xe2x80x94Oxe2x80x94CH2CH2-xcex2
xcex1-CH2xe2x80x94CH2NHCOCH2xe2x80x94Oxe2x80x94CH2CH2-xcex2
xcex1-CH2xe2x80x94(CH2xe2x80x94CH2xe2x80x94O)yxe2x80x94(CH2)3NHCOxe2x80x94CH2xe2x80x94Oxe2x80x94CH2CH2-xcex2 with y=1-6
xcex1-CH2NHCO(CH2)10xe2x80x94Oxe2x80x94CH2CH2-xcex2
xcex1-CH2CH2NHCO(CH2)10xe2x80x94Oxe2x80x94CH2CH2-xcex2
xcex1-CH2xe2x80x94Oxe2x80x94CH2xe2x80x94CH(OC10H21)xe2x80x94CH2xe2x80x94Oxe2x80x94CH2CH2-xcex2
xcex1-CH2xe2x80x94Oxe2x80x94C6H4xe2x80x94Oxe2x80x94CH2xe2x80x94CH2-xcex2
xcex1-CH2-C6H4xe2x80x94Oxe2x80x94CH2xe2x80x94CH2-xcex2
Quite especially preferred according to the invention are radicals L of the compounds that are mentioned in the examples of the description of this invention.
For U, the above-indicated radicals for L, and the radicals that are identified as preferred and especially preferred, as well as the radicals that are mentioned above for the meaning of alkylene and that are optionally preferred and especially preferred hold true, provided that no xcex1-position nitrogen atom and no terminal (xcex2-position) SO2 group or CO group need be present.
Preferred radicals B1 are hydrogen, straight-chain or branched C1-C10 alkyl radicals, which are optionally interrupted by 1-5 oxygen atoms, and/or are optionally substituted with 1-5 hydroxy groups, 1-2 COOH groups, a phenyl group that is optionally substituted by a COOH group, a benzyl group and/or 1-5 OR4 groups, with R4 in the meaning of a hydrogen atom or a C1-C3 alkyl radical.
Preferred radicals RF are straight-chain or branched perfluorinated alkyl radicals of formula CpF2pX, whereby 4 is equal to or less than p and p is equal to or less than 15, and X stands for a terminal fluorine atom.
The production of the compounds of general formula I according to the invention 
with
K in the meaning of a complexing agent or a metal complex of general formula II 
can be carried out according to the following processes:
Process A:
The carboxylic acid of formula III already contains metal ion equivalent R1: 
Carboxylic acid III that is optionally activated in situ with R1 in the meaning of a metal ion equivalent is reacted to an amide I with an amine IV in a coupling reaction.
This process for the production of metal complex carboxylic acid amides is known from DE 196 52 386.
The mixture of metal complex carboxylic acid III that is used in the coupling reaction, which optionally contains existing carboxy groups and/or hydroxy groups in protected form, and at least one solubilizing substance in an amount of up to 5, preferably 0.5-2 molar equivalents relative to the metal complex carboxylic acid, can be produced both in an upstream reaction stage and (e.g., by concentration by evaporation, freeze-drying or spray-drying of an aqueous or water-miscible solution of the components or by precipitation with an organic solvent from such a solution) are isolated and then are reacted in DMSO with a dehydrating reagent and optionally a coupling adjuvant and are formed in situ optionally by adding solubilizing substance(s) to the DMSO suspension from the metal complex carboxylic acid, dehydrating reagent and optionally a coupling adjuvant.
The reaction solution that is produced according to one of these processes is kept for pretreatment (acid activation) for 1 to 24, preferably 3 to 12 hours at temperatures of 0 to 50xc2x0 C., preferably at room temperature.
Then, an amine of general formula IV 
in which radicals R3, L, RF and A have the above-indicated meanings, is added without solvent or dissolved, for example, to dimethyl sulfoxide, alcohols, such as, e.g., methanol, ethanol, isopropanol or mixtures thereof, formamide, dimethylformamide, water or mixtures of the indicated solvents, preferably in dimethyl sulfoxide, water or solvents that are mixed with water. For amide coupling, the reaction solution that is thus obtained is kept at temperatures of 0 to 70xc2x0 C., preferably 30 to 60xc2x0 C., for 1 to 48, preferably 8 to 24 hours.
In some cases, it has proven advantageous to use the amine in the form of its salts, e.g., as hydrobromide or hydrochloride in the reaction. To release the amine, a base such as, e.g., triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, tripropylamine, tributylamine, lithium hydroxide, lithium carbonate, sodium hydroxide or sodium carbonate is added.
The optionally still present protective groups are then cleaved off.
The reaction product is isolated according to the methods that are known to one skilled in the art, preferably by precipitation with organic solvents, preferably acetone, 2-butanone, diethyl ether, ethyl acetate, methyl-t-butyl ether, isopropanol or mixtures thereof. The additional purification can be carried out by, for example, chromatography, crystallization or ultrafiltration.
As solubilizing substances, alkali salts, alkaline-earth salts, trialkylammonium salts, tetraalkylammonium salts, ureas, N-hydroxyimides, hydroxyaryltriazoles, and substituted phenols and salts of heterocyclic amines are suitable. By way of example, there can be mentioned: lithium chloride, lithium bromide, lithium iodide, sodium bromide, sodium iodide, lithium methane sulfonate, sodium methane sulfonate, lithium-p-toluenesulfonate, sodium-p-toluenesulfonate, potassium bromide, potassium iodide, sodium chloride, magnesium bromide, magnesium chloride, magnesium iodide, tetraethylammonium-p-toluenesulfonate, tetramethylammonium-p-toluenesulfonate, pyridinium-p-toluenesulfonate, triethylammonium-p-toluenesulfonate, 2-morpholinoethylsulfonic acid, 4-nitrophenol, 3,5-dinitrophenol, 2,4-dichlorophenol, N-hydroxysuccinimide, N-hydroxyphthalimide, urea, tetramethylurea, N-methylpyrrolidone, formamide as well as cyclic ureas, whereby the first five mentioned are preferred.
As dehdyrating reagents, all agents that are known to one skilled in the art are used. By way of example, there can be mentioned carbodiimide and onium reagents, such as, e.g., dicyclohexylcarbodiimide (DCCl), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide-hydroxychloride (EDC), benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (BOP) and O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), preferably DCCl.
In the literature, for example, the following suitable processes are described:
Aktivierung von Carbonsxc3xa4uren. xc3x9cbersicht in Houben-Weyl, Methoden der Organischen Chemie [Activation of Carboxylic Acids. Survey in Houben-Weyl, Methods of Organic Chemistry], Volume XV/2, Georg Thieme Verlag Stuttgart, 1974 (and J. Chem. Research (S) 1996, 302).
Aktivierung mit Carbodiimiden [Activation with Carbodiimides]. R. Schwyzer and H. Kappeler, Helv. 46: 1550 (1963).
E. Wxc3xcnsch et al., Vol. 100: 173 (1967).
Aktivierung mit Carbodiimiden/Hydroxysuccinimid [Activation with Carbodiimides/Hydroxysuccinimide]: J. Am. Chem. Soc. 86: 1839 (1964) as well as J. Org. Chem. 53: 3583 (1988). Synthesis 453 (1972).
Anhydridmethode, 2-Ethoxy-1-ethoxycarbonyl-1,2-dihydrochinolin [Anhydride Methods, 2-Ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline]: B. Belleau et al., J. Am. Chem. Soc., 90: 1651 (1986), H. Kunz et al., Int. J. Pept. Prot. Res., 26: 493 (1985) and J. R. Voughn, Am. Soc. 73: 3547 (1951).
Imidazolid-Methode [Imidazolide Method]: B. F. Gisin, R. B. Menifield, D. C. Tosteon, Am. Soc. 91: 2691 (1969).
Sxc3xa4urechlorid-Methoden, Thionylchlorid [Acid Chloride Methods, Thionyl Chloride]: Helv., 42: 1653 (1959).
Oxalylchlorid [Oxalyl Chloride]: J. Org. Chem., 29: 843 (1964).
As coupling adjuvants that are optionally to be used, all that are known to one skilled in the art are suitable (Houben-Weyl, Methoden der organischen Chemie, Volume XV/2, Georg Thieme-Verlag, Stuttgart, 1974). By way of example, there can be mentioned 4-nitrophenol, N-hydroxysuccinimide, 1-hydroxybenzotriazole, 1-hydroxy-7-aza-benzotriazole, 3,5-dinitrophenol and pentafluorophenol. Preferred are 4-nitro-phenol and N-hydroxysuccinimide; especially preferred in this case is the first-mentioned reagent.
The cleavage of the protective groups is done according to the processes that are known to one skilled in the art, for example by hydrolysis, hydrogenolysis, alkaline saponification of esters with alkali in aqueous-alcoholic solution at temperatures of 0xc2x0 to 50xc2x0 C., acid saponification with mineral acids or in the case of, e.g., tert-butylesters with the aid of trifluoroacetic acid [Protective Groups in Organic Synthesis, 2nd Edition, T. W. Greene and P. G. M. Wuts, John Wiley and Sons, Inc. New York, 1991], in the case of benzyl ethers with hydrogen/palladium/carbon.
The production of the starting material, the compounds of formula III, 
is known from DE 196 52 386.
The amines of general formula IV 
are commercially available products (Fluorochem, ABCR) or can be obtained according to the following process from compounds of general formula V by reaction with an amine of general formula VI and subsequent reduction of compounds of general formula VII: 
in which
RF, A, L and R3 have the above-mentioned meaning, and Lxe2x80x2 has the meaning of group L, in which the xcex1-CH2 group is absent, and
R4 stands for hydrogen or a methyl group.
According to the process that is already described above for the activation of carboxylic acid III that is disclosed in the literature, acid V is activated before the reaction with amine VI. For R4 in the meaning of a methyl group, an aminolysis is carried out.
The compounds of general formula V are commercially available products (Fluorochem, ABCR) or are produced as disclosed in DE 196 03 033.
The compounds of formula VI are commercially available products (Fluorochem, ABCR) or can be produced as described in Houben-Weyl, Methoden der organischen Chemie, XI/2 Stickstoff-verbindungen [Nitrogen Compounds], Georg Thieme Verlag Stuttgart, 1957, p. 680; J. E. Rickman and T. Atkins, Am. Chem. Soc., 96:2268, 1974, 96: 2268; F. Chavez and A. D. Sherry, J. Org. Chem. 1989, 54: 2990.
The compounds of general formula IV are obtained in a way that is known in the art [Helv. Chim. Acta, 77: 23 (1994)] by reduction of the compounds of general formula VII, for example, with diborane or lithium aluminum hydride and cleavage of the protective groups.
Process B
As starting material, the carboxylic acid of formula IIIa with R1 in the meaning of hydrogen is usedxe2x80x94it does not contain any metal ion equivalent R1. The carboxyl groups are protected according to the processes that are known to one skilled in the art, and a compound of formula IIIb is obtained, whereby R5 stands for any protective group. 
As carboxyl protective groups, e.g., straight-chain or branched C1-C6 alkyl, aryl and aralkyl groups, for example, the methyl, ethyl, propyl, butyl, phenyl, benzyl, diphenylmethyl, triphenylmethyl, bis(p-nitrophenyl)-methyl group as well as trialkylilyl groups are suitable. Prefered is the t-butyl group. 
The reaction of protected carboxylic acid IIIb with the amine of formula IV and the cleavage of the protective groups is carried out as described under process A, and in a subsequent step, carboxylic acid Ia that is obtained is reacted with at least one metal oxide or metal salt of an element of the desired atomic number, as is disclosed in, e.g., DE 195 25 924.
If the metal complex that is obtained from process A or B contains free COOH groups, these groups can also be present as salts of physiologically compatible inorganic or organic bases.
The neutralization of optionally still present free carboxy groups is then carried out with the aid of inorganic bases (for example hydroxides, carbonates or bicarbonates) of, for example, sodium, potassium, lithium, magnesium or calcium and/or organic bases, such as, i.a., primary, secondary and tertiary amines, such as, for example, ethanolamine, morpholine, glucamine, N-methylglucamine and N,N-dimethylglucamine, as well as basic amino acids, such as, for example, lysine, arginine and ornithine or amides of originally neutral or acidic amino acids.
For the production of neutral complex compounds, enough of the desired bases can be added to, for example, the acid complex salts in aqueous solution or suspension so that the neutral point is reached. The solution that is obtained can then be evaporated to the dry state in a vacuum. It is frequently advantageous to precipitate the neutral salts that are formed by adding water-miscible solvents, such as, for example, lower alcohols (methanol, ethanol, isopropanol, etc.), lower ketones (acetone, etc.), polar ethers (tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.) and thus to obtain easily isolated and readily purified crystallizates. It has proven especially advantageous to add the desired bases as early as during the complexing of the reaction mixture and thus to save a process step.
With the compounds according to the invention, higher blood concentrations are achieved than with extracellular contrast media. They are dispersed after i.v. administration only into the intravascular space, and they thus have a decisive advantage compared to the extracellular contrast media.
Better elimination from the blood via the kidneys ensures a small burden on the overall organism.
The compounds of this invention are distinguished by better compatibility, higher lymph node concentration in three successive lymph node stations (which is especially important for i.v. lymphography). They are thus especially well suited for use in MRT lymphography.
The compounds according to the invention are suitable for NMR diagnosis and x-ray diagnosis and for radiodiagnosis and radiotherapy.
The subject of the invention is therefore also the use of the compounds according to the invention for the production of a contrast medium for use in NMR diagnosis and x-ray diagnosis, for radiodiagnosis and radiotherapy.
Subjects of the invention are also pharmaceutical agents that contain at least one physiologically compatible compound of general formula I, optionally with the additives that are commonly used in galenicals.
The production of the pharmaceutical agents according to the invention is carried out in a way that is known in the art by the complex compounds according to the inventionxe2x80x94optionally with the addition of the additives that are commonly used in galenicalsxe2x80x94being suspended or dissolved in aqueous medium and then the suspension or solution optionally being sterilized. Suitable additives are, for example, physiologically harmless buffers (such as, for example, tromethamine), additives of complexing agents or weak complexes (such as, for example, diethylenetriaminepentaacetic acid or the Ca-complexes that correspond to the metal complexes according to the invention) orxe2x80x94if necessaryxe2x80x94electrolytes such as, for example, sodium chloride orxe2x80x94if necessaryxe2x80x94antioxidants, such as, for example, ascorbic acid.
If suspensions or solutions of the agents according to the invention in water or physiological hydrochloric acid solution are desired for enteral or parenteral administration or other purposes, they are mixed with one or more adjuvant(s) that are commonly used in galenicals [for example, methyl cellulose, lactose, mannitol] and/or surfactant(s) [for example, lecithins, Tween(R), Myrj(R)] and/or flavoring substance(s) for taste correction [for example, ethereal oils].
Basically, it is also possible to produce the pharmaceutical agents according to the invention without isolating the complexes. In any case, special care must be used to carry out the chelation so that the complexes according to the invention are practically free of non-complexed metal ions that have a toxic effect.
This can be ensured, for example, with the aid of color indicators, such as xylenol orange, by control titrations during the production process. The invention therefore also relates to a process for the production of the complex compounds and their salts. As a final precaution, there remains purification of the isolated complex.
In the in-vivo administration of the agents according to the invention, the latter can be administered together with a suitable vehicle, such as, for example, serum or physiological common salt solution and together with another protein, such as, for example, human serum albumin (HSA).
The agents according to the invention are usually administered parenterally, preferably i.v. They can also be administered intravascularly or interstitially/intracutaneously depending on whether bodily vessels or tissue are to be studied.
The pharmaceutical agents according to the invention preferably contain 0.1 xcexcmol-1 mol/l of the complex and are generally dosed in amounts of 0.0001-5 mmol/kg.
The examples below are used for a more detailed explanation of the subject of the invention, without intending that it be limited to these examples.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
In the foregoing and in the following examples, all temperatures are set forth uncorrected in degrees Celsius; and, unless otherwise indicated, all parts and percentages are by weight.
The entire disclosure of all applications, patents and publications, cited above, and of corresponding German application No. 199 14 101.0, filed Mar. 22, 1999, and U.S. Provisional Application Serial No. 60/128,623, filed Apr. 9, 1999, are hereby incorporated by reference.